Patients with schizophrenia present a 40% incidence of psychotic reactions following single administration of d-amphetamine (AMPH) at doses that are not psychotogenic in healthy subjects. AMPH being a potent dopamine (DA) releaser, this observation is consistent with the DA hypothesis of schizophrenia. However, the neuronal mechanism underlying this vulnerability is unknown. The aim of this study is to test the hypothesis that patients with schizophrenia exhibit increased intrasynaptic DA release following AMPH challenge. This hypothesis will be evaluated with single photon emission computerized tomography (SPECT). SPECT scanning will be performed during constant infusion with the D2 radiotracer [123I]IBZM, before and after administration of AMPH (0.3 mg/kg, i.v.). In baboons and in humans, we observed that AMPH reduced the [123I]IBZM equilibrium specific binding. This decreased binding following AMPH reflects a decrease in D2 receptor availability due to increased competition by endogenous DA. In baboons, we observed an excellent correlation between this effect and the AMPH induced extracellular DA release measured with microdialysis. In humans, the reduction in D2 availability correlated well with the subjective activation measured on self rating scales following AMPH. Thus, this paradigm allows measuring, in the same experiment, the baseline D2 binding potential, the reduction in D2 binding potential following AMPH, and the behavioral effects of AMPH. Preliminary data obtained in 8 unmedicated patients with schizophrenia and 8 healthy controls matched for age, sex, ethnic and socioeconomic background suggested increased intrasynaptic DA release after AMPH in schizophrenics compared to controls. This observation points toward dysregulation of the DA neurons in schizophrenia, but should be regarded with caution given the small sample size. Thirty neuroleptic free patients with schizophrenia, fifteen neuroleptic naive patients with schizophrenia and forty-five healthy controls matched for age, gender, ethnic and socioeconomic background will undergo the SPECT experiment with [123I]IBZM and AMPH challenge (0.3 mg/kg). Behavioral response to AMPH will be assessed and compared to the results of the SPECT experiment. This study will test the following hypotheses: 1) AMPH-induced DA release will be increased in the schizophrenic group compared to the control group; 2) in the schizophrenic group, the increase in positive psychotic symptoms following AMPH will be correlated with the magnitude of the DA release. These studies should provide important information regarding the pathophysiology of DA transmission schizophrenia.